tbuckley/cabot-search huggingface dataset:
Abstract 13626: The Glycolytic Enzyme Pyruvate Kinase M2 Regulates Deep Vein Thrombosis
Authors: Manasa K Nayak, Gagan Flora, Prakash Doddapattar, Anil K Chauhan
Journal: Circulation (2022)

Introduction: Current treatment regimen for deep vein thrombosis (DVT) includes anticoagulants or surgical intervention. While effective, anticoagulants exhibit a bleeding risk that limits their use. Activated platelets release pro-thrombotic chemokines such as platelet factor 4 (PF4) from their α-granules and are known to potentiate DVT via promoting neutrophil extracellular traps (NETs). Recently, we have shown that dimeric pyruvate kinase M2 (PKM2) regulates platelet function and arterial thrombosis without affecting hemostasis. However, the role of platelet-specific PKM2 in modulating NETosis and DVT remains unexplored. Methods: Susceptibility to DVT was evaluated in the flow-restricted inferior vena cava (IVC) stenosis model in PKM2 fl/fl PF4Cre +/- mice. The littermate PKM2 fl/fl PF4Cre -/- (abbreviated as PKM2 fl/fl ) was used as control. Next, we evaluated whether wild-type mice infused with a specific inhibitor of dimeric-PKM2, ML265, reduced DVT susceptibility in the IVC stenosis model. Results: The platelet-specific PKM2 -/- mice were less susceptible to DVT in the IVC stenosis model. The PF4 secretion from α-granules was significantly inhibited in agonist-stimulated platelets from PKM2 fl/fl PF4Cre+ mice compared to the platelets from PKM2 fl/fl mice. SNAP-23 phosphorylation regulates SNARE protein complex-mediated mediated secretion from α granules. Therefore, we determined the mechanistic role of PKM2 in modulating SNAP-23-mediated PF4 secretion in platelets. In agonist-stimulated PKM2-/- platelets, SNAP23 phosphorylation and PF4 secretion were reduced compared to agonist-stimulated WT platelets. In addition, neutrophils treated with stimulated platelet releasates from PKM2 fl/fl PF4Cre+ mice exhibited significantly reduced NET formation in contrast to PKM2 fl/fl mice. Finally, we demonstrate that ML265-treated mice showed reduced susceptibility to DVT in the IVC stenosis model. Conclusions: Our results suggest an essential role of PKM2 in regulating SNAP-23 mediated α-granule release, NETosis, and subsequent development of DVT.
Abstract 14052: Impact of Sex and Age on Left Ventricular Remodeling in Patients With Chronic Aortic Regurgitation
Authors: Emmanuel O Akintoye, Yoshihito Saijo, Lorenzo Braghieri, Osamah Badwan, Hardik Patel, M. Marwan Dabbagh, Christine L Jellis, Milind Y Desai, L L Rodriguez, Richard A Grimm, Brian P Griffin, Zoran B Popovic
Journal: Circulation (2022)

Introduction: Women and older patients with chronic aortic regurgitation (AR) have disproportionately higher rates of adverse events compared to men and younger patients, respectively. Yet, guidelines recommend same left ventricular (LV) dimension thresholds for intervention in all. While experimental animal models suggest different rates of LV remodeling by sex and age, there is paucity of data in humans with AR Methods: We included consecutive patients with isolated moderate or severe AR who were serially monitored by echo between 2010 &amp; 2016. The 2 main endpoints were change in LV volumes indexed to body surface area (LVEDVi &amp; LVESVi ) and adverse events (heart failure hospitalization, urgent surgery, or death) Results: 786 patients [mean (SD) age 58 (16) yrs &amp; 31% women] were included. Median (IQR) follow up was 25 (12-44) months. A moderate increase in LV volumes was observed overall, although women consistently had smaller LV volumes compared to men ( Fig 1 ). Similarly, compared to younger patients (&lt;60 yrs), older patients (≥60 yrs) persistently had smaller LV volumes ( Fig 1 ). Despite having smaller LV volumes, women and older patients were more sensitive to change in LV volumes, with higher rate of events per unit increase in volume e.g., HR per unit increase in LVEDVi was 1.01 (1.00-1.02) for men and 1.03 (1.01-1.07) for women ( P int =0.01) ( Fig 2 ) Conclusions: Independent of BSA, women and older patients with significant AR maintained smaller LV volumes than men and younger patients, respectively, on serial evaluation. Yet, they were more sensitive to change in LV volume. Sex and age-specific LV volume thresholds for timing of AR surgery are needed to address disparity in outcomes
Abstract 14415: Clinical Characteristics and Predictors of the “Good Fontan”: A Multi-Institutional Study
Authors: robert W elder, Anne M Valente, Brooke Davey, Fred Wu, Nancy A Drucker, Kristin Lombardi, Seohyuk Lee, Nicole St. Clair, Olga H Toro-salazar, Rahul Rathod
Journal: Circulation (2022)

Introduction: Fifteen-year survival after Fontan operation approaches 95%, but morbidities are increasingly prevalent. It is unknown how well cardiologists can predict which pts are at risk for major adverse events (MAE), but awareness is critical to enable appropriate counseling. We asked cardiologists the “surprise” question: would you be surprised if your patient has a MAE in the next year? Methods: We performed a prospective, multi-center study across New England. The attending cardiologist was asked the yes/no “surprise” question. Inclusion criteria included lateral tunnel or extracardiac Fontan and age &gt;10 yrs; individuals were excluded for current transplant evaluation, history of Fontan conversion, or pregnancy. Baseline clinical data were collected. After 12 months, cardiologists were surveyed to assess for MAE (see Table) and multivariate analysis (MVA) was performed for those deemed to be at risk and those with MAE. Results: From 2018-19, 146 pts and 40 cardiologists were enrolled at 9 sites. 99/146 pts (68%) were predicted to be a “Good Fontan.” After 1 yr, 17 (12%) patients experienced a MAE (Table). The simple kappa coefficient of ability to predict MAE was 0.17 (95% CI 0.02-0.32), suggesting ability to predict MAE was only 17% better than random chance. In MVA of those at risk (47/146), diuretic/beta blocker use (p=&lt;0.0001) and systolic dysfunction (p=0.0046) were associated with identified risk. MVA of pts who experienced MAE (n=17) found prior unplanned cardiac admission (p=0.0062), diuretic/beta blocker use (p=0.028) and significant AV valve regurgitation (p=0.049) to be associated with MAE. Conclusions: Cardiologists are only marginally able to identify which Fontan pts are at risk for MAE in the next year. There was overlap between factors associated with prediction of “at risk” group and MAE, namely use of diuretic/blocker and the linked systolic dysfunction/AV valve regurgitation, which merits close attention in follow-up and further study.
Abstract 13621: Genetic and Pharmacological Induction of Endothelial Sirt3 After Onset of Hypertension Rescues Endothelial Function
Authors: Anna Dikalova, Liliya Tkachuk, Mingfang Ao, Daniel Fehrenbach, Jack Arbiser, Sergey Dikalov
Journal: Circulation (2022)

Endothelial dysfunction plays critical role in the pathogenesis of hypertension and atherosclerosis. These pathological conditions are main risk factors for cardiovascular disease killing 700,000 people every year in US alone. We discovered a new control point with the potential to address this problem. We have shown that Sirt3 level is reduced in essential hypertension and endothelial Sirt3 overexpression attenuates endothelial dysfunction and hypertension. We proposed induction of endothelial Sirt3 after onset of hypertension to rescue endothelial function and reduce hypertension. To test the hypothesis, we used genetic- and pharmacological Sirt3 activation. To genetically induce the expression of endothelial Sirt3 we used Sirt3 flox/flox mice crossed with VeCad-Cre mice treated with low dose of 4-hydroxytamoxifen (4HOT, i.p. 0.3 mg/20 g daily, 5 days) which does not have off-target cardiovascular effects. Mice underwent telemetry placement and ten days later received 4-week osmotic pumps containing vehicle (saline) or angiotensin II (0.7 mg/kg/day). 14-days later half of mice received 4HOT to induce endothelial Sirt3 overexpression. Treatment of mice with 4HOT after onset of hypertension slightly reduced blood pressure but most importantly rescued endothelial-dependent relaxation, normalized mitochondrial O 2 . - and restored endothelial nitric oxide. Second, we tested if pharmacological induction of Sirt3 by hexafluoro (i.p. 8 mg/kg, 4 days) after onset of angiotensin II-induced hypertension improves endothelial function and reduces hypertension. It was found that hexafluoro substantially reduced systolic blood pressure, significantly diminished vascular mitochondrial O 2 . - and improved endothelial nitric oxide. To test the role of endothelial Sirt3 in pharmacological effect of hexafluoro we used endothelial specific Sirt3 knockout mice and angiotensin II model of hypertension. Interestingly, hexafluoro was not effective in endothelial Sirt3 deficient mice supporting specific role of endothelial Sirt3. These studies demonstrate therapeutic potential of genetic and pharmacological endothelial Sirt3 induction after onset of hypertension for treatment of endothelial dysfunction diminishing cardiovascular disease.
Abstract 12841: Overexpression of Scarna20 Promotes Small Nuclear RNA Pseudouridylation and Improves Cardiomyogenesis
Authors: Vinoth Sigamani, Selene G Perales, SHEEJA RAJASINGH, Rajasingh Johnson
Journal: Circulation (2022)

Introduction: Non-coding RNAs, particularly small Cajal body-associated RNAs (scaRNAs), play an important role in alternative splicing and maturation of mRNAs through pseudouridylatory modification. Our small non-coding RNA sequencing analysis has identified that scaRNA20 plays a major role in cardiomyocyte differentiation. In this study, we aim to elucidate the role of scaRNA20 during cardiac differentiation using in vitro induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMC) subjected to 3% hypoxic conditions. Hypothesis: Overexpression (OE) of scaRNA20 in iPSCs leads to enhanced cardiomyogenesis and increases the endurance properties of cardiomyocytes by maintaining contractility under hypoxic conditions. Methods and results: We have used OE and knockdown (KD) assays to delineate the role of scaRNA20 during the process of iPSC to iCMC differentiation. The video recordings of scaRNA20-OE-iCMCs and scaRNA20-KD-iCMC contractilities were measured by a novel Particle Image Velocimetry (PIV) method. Our results show that the contractility was impaired in control iCMCs whereas in scaRNA20-OE-iCMCs it was well-maintained under the hypoxic conditions. In contrast, scaRNA20-KD-iCMCs resulted in poor differentiation, they were non-functional and had an impaired contractility. Furthermore, we investigated the pseudouridylation levels of spliceosomal RNA U12 which is a direct target for scaRNA20. We found an increased level of Ψ 28 in scaRNA20-OE iCMCs (Figure A-D) . In addition, the scaRNA20 overexpression in iCMCs resulted in the upregulation of DKC1, NHP2, and NOP10 and downregulation of GAR1, COIL, and WRAP53 and these effects regulate the activation of pTP53 and STAT3 and thus activating cardiac genes. Conclusion: Taken together, our results show for the first time that modulation of iCMCs with scaRNA20 helps maintain the endurance properties of cardiomyocytes while under hypoxic conditions, and it also improves cardiomyogenesis.
Abstract 12755: Role of Micriobiome-Derived Short-Chain Fatty Acid Butyrate in Pulmonary Hypertension
Authors: Andres Pulgarin, Barbara Methe, Alison Morris, Imad Al Ghouleh
Journal: Circulation (2022)

Introduction: Pulmonary hypertension (PH) is a progressive, severe disease characterized by high blood pressure in the pulmonary circulation, inflammatory cells infiltration and excessive pulmonary vascular remodeling. Endothelial cell (EC) dysfunction is increasingly recognized as a precipitating event for this remodeling. Butyrate, a microbiome-derived molecule with histone deacetylation activity and present in circulating blood, has been associated with benefit in atherosclerosis and associated cardiovascular diseases. Due to a dearth of knowledge on the role of microbiome-derived molecules in PH-EC, we aimed to test whether butyrate plays a protective role in EC under PH. Results: Mice supplementation with butyrate (sodium butyrate, NaB) attenuated hypoxia-induced right ventricular (RV) pressure (43±2 to 35±3 mmHg, p&lt;0.05) and RV hypertrophy (RV/LV+Septum= 0.43±0.008 to 0.38±0.01, p&lt;0.05) in vivo. NaB also lowered hypoxia-induced circulating monocyte numbers and reduced gene expression of inflammatory adhesion molecule VCAM-1 in hypoxic lung-derived CD31+ ECs, as well as increased expression of ERM binding Phosphoprotein 50 (EBP50), a protein we have shown to modulate endothelial reprogramming in PH. In vitro, NaB attenuated PH-related inflammatory cytokine IL1β-induced human pulmonary arterial EC (HPAEC) migration at 48 h. Consistently, NaB also reversed IL1β-induced increase in VCAM-1 expression at the mRNA and protein level in HPAEC. Moreover, NaB rescued the expression of IL1β-induced reduction in cell surface protein integrin α3, EBP50, and Vangl2 (Van Gogh-like) protein, a member of planar cell polarity core whose downregulation has been linked to PH. Conclusions: Collectively our results demonstrate that butyrate attenuates PH potentially via protecting against myeloid cell induction and pathophysiological proinflammatory, promigratory pulmonary vascular EC activation. Butyrate may also reduce EC reprogramming through its effects on EBP50, and may promote pulmonary vascular homeostasis through Vangl2 induction. These findings support the potential for therapeutic benefits of butyrate in PH and the need for further investigation of the role of microbiome-derived metabolites in this devastating disease.
Abstract 12697: Pharmacological Inhibition of BAG3-HSP70 With the Proposed Breast Cancer Therapeutic JG-98: In-vivo Mice Study
Authors: Hasitha D Manohar, Emily Ma, Quan Cao, Maria Papadaki, Clodia Osipo, Jonathan A Kirk
Journal: Circulation (2022)

Introduction: The co-chaperone Bcl2-associated athanogene-3 (BAG3), along with its cofactor heat shock protein 70 (HSP70), is fundamental for protein quality control and cell survival in a healthy heart. However, elevated expression of BAG3 is also associated with metastasis in breast and other cancers, and small molecules such as JG-98 that disrupt BAG3-HSP70 binding have been shown to reduce cancer cell proliferation. We previously showed JG-98 is cardiotoxic in neonatal rat ventricular myocytes. Hypothesis: As BAG3-HSP70 is fundamental for autophagic protein turnover, JG-98 will reduce tumor size but have cardiotoxic effects. Methods: BT474 Resistant breast cancer cells were injected bilaterally into mammary fat pads of female athymic nude mice. When tumors reached 25 mm 2 , mice received a baseline echocardiography and were randomized to intraperitoneal injections of either PBS/DMSO vehicle or 3 mg/kg JG-98 twice weekly for 3 weeks (n = 4/group) or 6 weeks (n=10/group). Tumor growth was monitored using calipers and echocardiography was performed prior to sacrifice. Results: After 3 weeks, tumor volume increased by ~44% in Vehicle treated mice but decreased by 17% in JG-98 treated mice, effectively halting tumor growth. However, cardiac echocardiography did not reveal any functional or structural differences between the vehicle and JG-98 treated mice after either 3 or 6 weeks. JG-98 did result in dysregulation of BAG3 and its interactome in the LV. JG-98 slightly increased BAG3 levels in the LV at 3 weeks, but slightly decreased levels at 6 weeks. This agrees with data showing acute stress upregulates BAG3, but chronic stress downregulates it. Similarly, we found altered protein expression of the BAG3 binding partners HSBP8, HSPB5, and HSP70. Conclusions: JG-98 had no overt cardiotoxic effects, suggesting the adult heart may be resistant to disrupted BAG3-HSP70. However, we also observed dysregulated protein levels in the BAG3-mediated autophagy pathways that could precede dysfunction with more chronic treatment. Furthermore, mutations in BAG3 or altered expression levels could sensitize individuals to JG-98 treatment. Further work is necessary to understand the cardiac impact of cancer therapeutics that target BAG3.
Abstract 13196: Inter-Stage Infants With Single Ventricle Heart Disease Show Prominent Dysregulation in Multiple Metabolic Pathways: A Targeted Metabolomics Analysis
Authors: Benjamin S Frank, Ludmila Khailova, Jonathan Dekermanjian, Max B Mitchell, Gareth J Morgan, Mark Twite, Uwe Christians, Michael V Di Maria, Jelena Klawitter, Jesse Davidson
Journal: Circulation (2022)

Objectives: To evaluate the circulating metabolome of interstage infants with single ventricle heart disease (SVHD) and determine whether metabolite levels were associated with pulmonary vascular inadequacy. Background: Infants with SVHD experience morbidity related to pulmonary vascular inadequacy. Metabolomic analysis involves a systems biology approach to identifying novel biomarkers and pathways in complex diseases. The metabolome of infants with SVHD is not well understood and no prior study has evaluated the relationship between metabolite levels and pulmonary vascular readiness for staged SVHD palliation. Methods: Prospective cohort study of 52 infants with SVHD undergoing Stage 2 palliation and 48 healthy infants. Targeted metabolomic phenotyping (n=175 metabolites) performed by tandem mass spectrometry on SVHD pre-Stage 2, post-Stage 2, and control serum samples. Clinical variables were extracted from the medical record. Results: Random Forest analysis readily distinguished between cases and controls (Figure), and pre-op and post-op samples. Seventy-four of 175 metabolites differed between SVHD and controls. Twenty-seven of 39 metabolic pathways were altered including pentose phosphate and arginine metabolism. Seventy-one metabolites differed in SVHD patients between timepoints. Thirty-three of 39 pathways were altered post-operatively including arginine and tryptophan metabolism. We found trends towards increased pre-operative methionine metabolites in patients with higher pulmonary vascular resistance and higher post-operative tryptophan metabolites in patients with greater post-operative hypoxemia. Conclusions: The circulating metabolome of interstage SVHD infants differs significantly from controls and is further disrupted after Stage 2. Several metabolites showed promising trends towards association with adverse outcomes. Metabolic dysregulation may be an important factor in early SVHD pathobiology.
Abstract 13435: Utilization of Primary Prevention Implantable Cardioverter Defibrillator (ICD) Among Older Patients With Hypertrophic Cardiomyopathy (HCM): A Real World Analysis
Authors: Sarah A Goldstein, kevin kennedy, Daniel Friedman, Sana M Al-Khatib, Andrew Wang
Journal: Circulation (2022)

Introduction: Guidelines differ for the use of primary prevention ICDs among patients with HCM, with particular ambiguity among older patients (age &gt; 65). This analysis examined the utilization of primary prevention ICDs among older patients with HCM. Methods: NCDR ICD was queried to identify patients with HCM who received a primary prevention ICD between 2010-2016. Patient characteristics were reported overall and by age category. Trends in ICD utilization and relevant patient characteristics were assessed over time. Results: Of 5571 patients with HCM who were included, 1511 (27.1%) were &gt; 65 years old. In comparison with younger HCM patients, those &gt; 65 had higher NYHA class (III-IV 18.9% vs 12.3%, p&lt;0.001), and more frequently had cardiovascular and non-cardiovascular co-morbidities (atrial fibrillation (40.6% vs 19.8%, p&lt;0.001), ischemic heart disease (24.3% vs 8.3%, p&lt;0.001), valvular disease (12.5% vs 7.2%, p&lt;0.001), hypertension (79.2% vs 49.5%, p&lt;0.001), cerebrovascular disease (12.3% vs 6.5%, p&lt;0.001), chronic lung disease (15.0% vs 7.6%, p&lt;0.001) and diabetes mellitus (23.2% vs 12.5%, p&lt;0.001). Analyzing risk factors for sudden cardiac death (SCD), older patients had a lower prevalence of family history of SCD (20.3% vs. 30.1%), but a higher prevalence of syncope (34.3% vs 31%, p=0.019), NSVT (50.7% vs. 38.6%) and reduced LVEF (23.1% vs. 15.3%) (p&lt;0.001 for all). ICD utilization increased over time in all age groups, but represented a similar percentage of the overall HCM cohort irrespective of age. There were no changes in the prevalence of risk factors for SCD over time (Figure). Conclusions: Older patients who received a primary prevention ICD had more cardiovascular and non-cardiovascular comorbidities and higher rates of certain SCD risk factors compared with younger patients with HCM. ICD utilization among older patients with HCM increased over time at a similar rate as observed among younger patients despite stable a prevalence of SCD risk factors.
Abstract 14136: Diagnosis and Prognosis of Type 2 Myocardial Infarction Using Objective Evidence of Myocardial Ischemia
Authors: Jonathan D Knott, Olatunde Ola, Laura De Michieli, Ashok Akula, Ramila Mehta, David Hodge, Rajiv Gulati, Allan S Jaffe, Yader Sandoval
Journal: Circulation (2022)

Introduction: Differentiating type 2 myocardial infarction (T2MI) from myocardial injury can be difficult. The presence of objective evidence of acute myocardial ischemia may facilitate the identification of high-risk T2MI patients. Methods: Retrospective, observational cohort post-hoc analysis of adult emergency department patients undergoing hs-cTnT measurement. Patients with ≥1 hs-cTnT&gt;99th percentile were adjudicated following the Fourth Universal Definition of MI. Patients were categorized as “subjective T2MI” when ischemic symptoms were the lone criteria supporting T2MI, or “objective T2MI” when there was ≥1 objective clinical feature (electrocardiography, imaging, angiography) of acute myocardial ischemia. The primary outcome was mortality. Results: A total of 857 patients were included, amongst which 55 (6.4%) were classified as subjective T2MI, 36 (4.2%) as objective T2MI, and 702 (82%) as myocardial injury. Among objective T2MIs, the most common criteria were ischemic electrocardiographic changes (n=29). Median (IQR) maximum hs-cTnT were 24 (18, 43) ng/L in myocardial injury, 34 (19, 80) in subjective T2MI, and 74 (35, 237) in objective T2MI. Those with objective T2MI had a higher risk of mortality during the index presentation (17% vs. 1.7%, p&lt;0.0001; HR 11.1 95% CI 3.7-33.4) and at 2-year follow-up (47% vs. 31%, p=0.04; HR 1.92, 95% CI 1.17-3.14) than those with myocardial injury (Figure). Objective T2MI had a higher mortality than subjective T2MI at index presentation (17% vs. 2.0%, p=0.01) and at 1- (25% vs. 9.1%, p=0.04) and 3-months (31% vs. 13%, p=0.04) follow-up. There were no mortality differences between subjective T2MI and myocardial injury. Conclusions: In patients diagnosed with T2MI, those with objective evidence of myocardial ischemia have significantly worse outcomes compared to those with myocardial injury and subjective T2MI. A more rigorous definition of T2MI might be a more effective way to define this important entity.